In this study, the mechanism involved in the anorectic effect of d-fenfluramine and CM 57 277 was investigated. Repeated injections of these two anorectic drugs resulted in elevation of hypothalamic met5-, leu5-enkephalin and Beta-endorphin. This increase is associated with reduction in body weight. The effect of these two anorectics can be reversed by metergoline, a serotonin receptor antagonist. The results suggest that decreased utilization of hypothalamic opioid peptides caused by a facilitation of serotonergic transmission may be responsible for the anoretic action of fenfluramine and CM 57 277 but not that of amphetamine. Met5-enkephalin release was also investigated in this study. The interaction between serotoninergic and endogenous opioid system and the importance of endogenous opioid peptide in eating behavior are well demonstrated in this study. These findings may aid in understanding the abnormal eating behavior. The interaction of met5-enkephalin and other transmitter, substance P, was also investigated in this study. Met5-enkephalin can be released from periaqueductral grey slices by substance P suggesting that substance P analgesia may be mediated by opioid peptide. The release of opioid peptide(s) from periaqueductal grey slices will be further characterized.